Normal amounts of amniotic fluid must be present in order for the fetus to grow and develop normally. Oligohydramnios (too little amniotic fluid) occurs in approximately 5 percent of human pregnancies and is responsible for many emergency cesarean sections, in utero fetal deaths due to cord compression, and neonatal deaths due to respiratory distress. Although it is widely assumed that fetal hypoxia causes oligohydramnios, the effects of hypoxia on amniotic fluid volume have not been studied experimentally. Indirect evidence suggests that fetal hypoxia may actually cause polyhydramnios (too much amniotic fluid) rather than oligohydramnios. The proposed studies will determine the effects of hypoxia on amniotic fluid volume in fetal sheep and explore the mechanisms of these effects. The overall hypothesis is that fetal hypoxia produces polyhydramnios and that fetal hypoxia in combination with placental insufficiency causes oligohydramnios. In Specific Aim number 1, fetal hypoxia will be produced by progressive fetal anemia (anemic hypoxia). The hypothesis is that there will be a threshold at which a large increase in amniotic fluid volume occurs and this is dependent upon elevated fetal plasma lactate and arginine vasopressin levels. In Specific Aim number 2, the fetus will be made hypoxic by reducing the inspired oxygen content of the mother (hypoxic hypoxia). The hypothesis is that polyhydramnios will develop and the associated mechanisms are the same as occur during anemic hypoxia. In Specific Aim number 3, the fetus will be made hypoxic by repeated microsphere embolizations of the umbilical circulation. The hypothesis is that this combination of fetal hypoxia and placental insufficiency will produce oligohydramnios. For each of these Specific Aims, the associated mechanisms will be studied by monitoring fetal urine production, fetal swallowing, lung liquid secretion, and the volume of amniotic fluid absorbed via the intramembranous pathway. Specific changes in each of these four flows are hypothesized for each method of creating fetal hypoxia. We expect the changes in amniotic fluid volume to be accurately predicted from the four measured flows. Overall, the proposed studies are important because they will dramatically improve our understanding of amniotic fluid volume regulation in the fetus under normoxic and hypoxic conditions. This is relevant clinically because an increased understanding of the mechanisms which regulate amniotic fluid volume should lead to better therapies for maintaining normal amniotic fluid volumes during human pregnancy and this would help reduce fetal and neonatal morbidity and mortality.